A single nucleotide polymorphism has been correlated with human populations at increased risk for drug and alcohol abuse. Affected individuals carry a variant form of fatty acid amide hydrolase, an enzyme responsible for setting cannabinoid tone in the brain. Biochemical data on this point mutant have revealed no significant deviations from its wild-type counterpart. However, fluids samples from affected individuals have revealed that carriers of this mutation express levels of this enzyme at roughly half that of wild-type cohorts. Could this observation provide an explanation for the observed drug abuse behaviors, or does this mutation manifest its effects in unpredicted ways? The only clear way to address these questions is to create a living model system. This proposal seeks to create a mouse harboring the same mutation found in the human population studies. Once this "knock-in" mouse is engineered, a series of behavioral tests will be used to determine if the animals replicate the drug abuse behaviors correlated in humans. Further, possible mechanisms to explain these behaviors will be sought. These mechanisms include the possible alteration of endogenous cannabinoid tone and/or the selective dysregulation of individual fatty acid amide metabolites. If this mouse model is found to exhibit increased susceptibility to drug abuse behaviors, it will provide a very powerful platform for future research into the evolution of these behaviors and possible means of pharmacological intervention. The National Institute on Drug Abuse has called drug abuse and addiction "one of America's most challenging public health problems", rivaling both diabetes and cancer in terms of costs to society. Identifying genetic contributions to drug abuse behaviors can provide powerful insights into etiology and may one day offer personalized treatment options for those at risk for these health concerns. [unreadable] [unreadable] [unreadable]